Heterosexual transmission of HIV is the primary route in women, who now account for 50% of those infected. In the absence of an effective vaccine, other modes of prevention are needed. A safe and effective topical microbicide will allow women and men to play a more direct role in their own protection. As with therapeutic approaches to HIV, a topical microbicide that combines compounds with differing modes of action will have an advantage in blocking the complex interactions that occur in the mucosa at the time of transmission. Many women at risk who will use the compounds will not know their HIV status. Therefore, a microbicide approach must consider the impact of exposure of infected women to the compound and therefore topicals that do not represent major therapeutic antiretrovirals might be an advantage. Given the evidence that HSV enhances HIV transmission, agents that also impact on other STI will have an added benefit. This approach must be safe and not interfere with natural barriers to infection. The approach to the advancement of candidate microbicides proposed in this program takes into account each of these issues. We are proposing to advance the development of the novel compound SAMMA to formulated product that will include an acid buffer to combine the entry inhibitory activity of SAMMA with the direct effects of an acid pH on the virus. We will also explore the potential of other compounds such as novel persulfated molecular umbrellas (pmu) as well as cdk inhibitors. Both classes of compounds have activity against HIV and HSV. Each of these approaches will be carefully studied focusing not only on advancing candidate compounds but broadening our understanding of the interaction between critical host defenses and topical microbicides. Carefully planned pilot clinical evaluation of compounds already in clinical trials (cellulose sulfate, acidform and tenofovir) as well as the proposed formulated SAMMA will focus on the effects of these compounds on innate immunity as well as the development of surrogate markers for efficacy.